The Candidate is a pediatric cardiologist who is completing a post-doctoral research fellowship in cardiovascular genetics and developmental biology to gain the skills necessary to pursue an academic career in patient-oriented research. His long-term goal is to become an independent physician scientist, and to contribute to the understanding of the molecular mechanisms underlying pediatric heart disease. By applying the complementary approaches of human genetics and cardiac development, he will cultivate a 'bedside to bench to bedside" approach to investigate the genetic causes and pathogenesis of pediatric aortic valve disease. Such an approach promises to provide a foundation for developing improved and novel diagnostic modalities, therapeutic interventions and preventive strategies for this important clinical problem. The objective of this proposal is to identify new genetic loci linked to aortic valve malformation and to elucidate the pathogenesis of pediatric aortic valve disease. The central hypothesis is that aortic valve disease pathogenesis is mediated by gene mutations that regulate extracellular matrix (ECM) organization during valve development thereby resulting in valve disease. Using families identified by a hypoplastic left heart syndrome (HLHS) proband, parametric and nonparametric linkage analysis will be performed to identify aortic valve disease-causing genes. The hypothesis is that HLHS is a severe form of aortic valve disease and is inherited as an autosomal recessive form of bicuspid aortic valve (BAV). Using explanted pediatric BAVs, the relationship between BAV morphology, ECM organization and valve disease type will be determined. To better define dysregulation of ECM remodeling as a cause of pediatric aortic valve disease, mechanistic analyses of ECM organization will be performed using a mouse model of elastin haploinsufficiency. The hypothesis is that elastin haploinsufficiency mediates dysregulation of ECM protein synthesis resulting in valve ECM disorganization and valve dysfunction. The rationale for the proposed studies is based upon preliminary data. Successful completion of the proposed studies will advance our understanding of pediatric valve disease. The Candidate is dedicated to a research career in pediatric cardiovascular medicine. His environment is exceptionally supportive as evidenced by an invested and accomplished Mentor and a generous and collaborative research environment renowned for its molecular and clinical cardiology programs. These factors create an ideal environment for professional development. A Career Development Award will allow the Candidate to devote 80% effort to patient-oriented research, and to obtain the training necessary to transition to an independent investigator. (End of Abstract)